This invention relates generally to treatment of Gram-positive bacterial infections and associated disease states, and in particular to use of genetically engineered or purified macrophage scavenger receptor protein for treating Gram-positive infections.
Infection from either Gram-negative or Gram-positive bacteria may be associated with a myriad of pathophysiological disease states. For example, infection with either type of microorganisms may result in septicemia and septic shock.
The bacterial components responsible in large part for the pathophysiological phenomena associated with Gram-negative infections, including septic shock, are endotoxin and its toxic component, lipid A. Endotoxins are the lipopolysaccharides uniquely found on the outer surface of Gram-negative bacteria. The outer monolayer of the outer membrane of most Gram-negative bacteria includes a unique hydrophobic component called lipid A, which is the active moiety of endotoxin.
In septic shock resulting from Gram-negative bacteria, endotoxin, or lipid A, activates phospholipases that degrade cell membrane phospholipids to liberate arachidonic acid that can initiate synthesis and release of leukotrienes, prostaglandins, thromboxanes, and other inflammatory mediators. Infusion of Gram-negative bacteria or endotoxin also stimulates release of catecholamines, glucocorticosteroids, histamine, serotonin, and other vasoactive substances. Further, lipid A and its precursor lipid IV.sub.A are potent activators of monocytic macrophages, in which they stimulate the rapid production of a wide array of immune mediators such as interleukin-1, tumor necrosis factor, and platelet activating factor. These inflammatory mediators have major influences on basic motor tone, microvascular permeability, and the aggregation of leukocytes and platelets, through their effects on endothelial and other cells and the generation of biologically active fragments of complement proteins.
Gram-negative bacterial endotoxin and its toxic component, lipid A, play a critical role in the genesis of endotoxin-induced septic shock. They activate phospholipases which degrade cell membrane phospholipids to liberate inflammatory mediators, which then affect microvascular permeability and the aggregation of leukocytes and platelets through the generation of complement factors. These interaction of proteins converts the endothelial cell surface from an anti- to a procoagulant state that permits intravascular coagulation. Endothelial cells lose their ability to selectively regulate permeability to small physiologic molecules, such as water and nutrients, and, under selected conditions, to larger molecules of blood such as plasma proteins. The cells swell and allow fluid to leak into surrounding tissues, causing hypoxia and parenchymal damage.
Endotoxin and lipid A also participate in the activation of macrophages, stimulating the production and release of cytokines, including interleukin-1 and tumor necrosis factor, which also have significant roles in the syndrome of septic shock with Gram-negative organisms.
Endotoxins and other ligands are bound by scavenger receptors on monocytic macrophages and have been shown to be rapidly cleared from the circulation. Scavenger receptors are homotrimeric integral membrane proteins that bind to diverse, high affinity, polyanionic ligands including (1) chemically modified proteins such as acetylated and oxidized low density lipoprotein (LDL) and maleylated bovine serum albumin (M-BSA), but not their unmodified counterparts; (2) certain polysaccharides such as dextran sulfate, but not chondroitin sulfate; (3) four-stranded polynucleotides including poly G and poly I, but not one- or two-stranded polynucleotides; (4) some anionic phospholipids such as phosphatidylserine; and (5) other macromolecules such as polyvinyl sulfate and crocidolite asbestos.
The combined effects of the vasoactive substances and inflammatory mediators in septic shock are body temperature extremes, altered mental status, decreased urine output, a decreased serum albumin concentration, tachypnea with hypoxemia, tachycardia, hypotension, and eventual circulatory collapse. The high morbidity associated with endotoxin-induced shock remains a major clinical problem, especially in debilitated and immunosuppressed patients such as hospitalized patients with underlying diseases that render them susceptible to blood stream invasion, catheterized and surgical patients, neonates, childbearing women, and elderly men with prostatic obstruction. For a review of septic shock, see D. C. Dale and R. G. Petersdorf, "Septic Shock," Harrison's Principles of Internal Medicine 474-478, 11th ed., E. Braunwald et al. eds. (1987).
Septic shock may also result from Gram-positive bacterial infections, notably those due to staphylococci, pneumococci, and streptococci. The mechanisms involved in the genesis and progress of Gram-positive septic shock are less clearly defined and understood than in Gram-negative septic shock. Nonetheless hemodynamic parameters are similar, cytokine (TNF, IL-1) induction is analogous and manifestations of organ damage are the same. The main difference in treatment between Gram negative and Gram positive septicemia is that people have focused on endotoxin rather than the Gram positive bacterial components.
Inhibitors and antagonists of the vasoactive substances involved in septic shock, plasma volume expanders, antiinflammatory and other immune system drugs, and various anti-prostaglandins have been used experimentally and clinically to alter the course of septic shock. Such measures have been only partially successful in controlling the morbidity associated with septicemia and septic shock. Because the pathology proceeds rapidly, treatment of patients must be initiated quickly, and suitably rapid differential diagnosis of Gram-positive and Gram-negative septicemia usually has not been possible because fast diagnostic methods have not been available. Therefore, patients who have been treated with compositions that are effective against Gram-negative but not Gram-positive bacteria do not benefit from the treatment. An example of such a composition is Centoxin.TM., developed by Centocor Pharmaceuticals. Although initial studies demonstrated efficacy against patients with septicemia, larger scale trials were not construed to be effective because of the lack of efficacy in treating patients with Gram-positive septicemia. Further, effective methods and compositions for treating Gram-positive septicemia have not been available generally. Accordingly, what is needed are methods and compositions for use in treating septicemia and associated disease states.
It is therefore an object of the present invention to provide compositions and methods of use to treat septic shock, caused by Gram-positive and/or Gram-negative bacteria.
It is another object of the present invention to provide a method to identify compositions useful in the treatment of septic shock, caused by Gram-positive and/or Gram-negative bacteria.